Ferroptosis is regarded as a promising cancer therapeutic target. As a major bioactive compound from traditional Chinese medicine (TCM) herb Sophora flavescens Aiton, oxymatrine (OMT) can depress inflammatory factors, reduce iron deposition, and suppress the hub gene or protein expression involved in ferroptosis and inflammation. Additionally, OMT can control collagen deposition in the liver and has a therapeutic effect on liver cancer. This research investigated the action mechanism of the mechanism of the effect of OMT on the process of liver cancer. OMT triggered cell death and restrained cell proliferation in liver cancer cells, along with downregulated levels of Yin Yang 1 (YY1) and glutathione peroxidase 4 (GPX4) and elevated expression of silent information regulator 1 (SIRT1). Moreover, ferroptosis is the main method leading to OMT-induced liver cancer cell death. OMT-induced ferroptosis was reversed after GPX4 and YY1 overexpression or inhibition of SIRT1. Furthermore, the OMT restrained tumor growth through the SIRT1/YY1/GPX4 axis in liver cancer transplantation models. These results indicated that OMT inhibited cell viability and induced ferroptosis of liver cancer cells, involving the regulatory mechanism of the SIRT1/YY1/GPX4 axis.